GH therapy in juvenile chronic arthritis: results of a two-year controlled study on growth and bone.

Disturbance of growth frequently occurs in children suffering from juvenile chronic arthritis (JCA). Recognition of growth impairment is important because reduced final height is one of the permanent consequences. The aim of this study was to evaluate the efficacy and safety of human GH (hGH) in growth-retarded prepubertal children with JCA. Thirty-five children were tested for GH deficiency (GHD) and randomly assigned to a study and an untreated control group; five were GH deficient and were part of the GHD group. All received glucocorticoids. The study group was treated with 1 IU/kg BW.wk hGH; the GHD group was given 0.5 IU. During 2 yr of hGH treatment growth velocity and height SD score increased compared with baseline values. There was a marked increase in growth velocity in the treated groups, but also some increase in the control group. Plasma levels of IGF-I and IGF-binding protein-3 increased with GH treatment. These results suggest that hGH might be useful in the treatment of growth impairment in JCA. GH may counteract the adverse effects of glucocorticoid therapy, but its effect is dependent on the disease activity. Long-term controlled studies are needed to determine the risks and benefits of GH therapy in JCA.

Susceptible and protective major histocompatibility complex class II alleles in early-onset pauciarticular juvenile chronic arthritis.

Oligonucleotide typing for alleles of the MHC loci DRB1, DQA1, and DQB1 was performed in 160 patients suffering from EOPA, JCA (or JRA = juvenile rheumatoid arthritis). Allele and haplotype frequencies of the patients were compared with the data of an unrelated healthy control group consisting of 200 individuals. Analysis of frequencies shows that HLA alleles are associated not only with susceptibility to EOPA-JCA but also with protection from the disease. The presence of protection connected with certain HLA alleles was assessed using a calculation which takes into account the condition that if one allele is increased, all other alleles of the same locus must be decreased in compensation. Protection can be assumed only in cases where a given allele has an observed frequency which is significantly beyond the expected compensatory decrease. Thus a hierarchy of associations was observed in EOPA-JCA patients. The alleles of the haplotypes DRB1*11 (12)-DQA1*0501-DQB1*0301 as well as DRB1*08-DQA1*0401-DQB1*0402 were found to be associated with susceptibility to disease, whereas the alleles DRB1*07 and DQA1*0201 converge with significant protection from the disease. Whereas the association with disease susceptibility seems to depend on a sequence motif encoded in certain DQA1 alleles, protection is associated either with alleles of DRB1 or DQA1.

Sera from JRA patients contain antibodies against a defined epitope in chromosomal protein HMG-17.

Autoantibodies against the nonhistone nucleosomal protein HMG-17 have been detected in a high percentage of ANA-positive patients with pauciarticular-onset JRA4. Here we report on the epitope mapping of the HMG-17 autoantigen with a set of overlapping and nested synthetic peptides spanning the entire amino acid sequence of the human HMG-17 protein. Competition ELISA experiments defined a proline and lysine rich octapeptide PKPEPKPK as the major epitope recognized by more than 70% of the HMG-17 positive JRA sera. Point mutations introduced in the autoimmune peptide determined the amino acid residues important for autoantibody recognition. Computer based sequence comparison shows close homology between the HMG-17 autoimmune epitope and certain infectious organisms, supporting the possibility that molecular mimicry is an important factor in the etiology of JRA.

Pain in juvenile chronic arthritis: consequences for the musculo-skeletal system.

Pain in juvenile chronic arthritis is underestimated. Children often don't verbalize their pain adequately. On a pain scale they usually grade pain lower than adults. Pain perception always depends on subjective factors, especially the child's stage of development. The younger the child the more nonverbal pain expressions dominate. Malpositioning of involved joints or abnormal patterns of movement are often the only signs of pain. This is demonstrated in an inquiry directed to the parents of 111 small children with different subgroups of juvenile chronic arthritis. In a reflex reaction children bring their inflamed joints into a pain relieving position. This triggers a vicious circle which may result in joint deformity and permanent handicap. Arthritis interferes with the child's activities. Behavioural changes and finally developmental disturbances can follow.

Functional joint analysis of the foot in juvenile chronic arthritis.

In juvenile chronic arthritis, foot joints become affected relatively frequently. Depending on the pattern of joint involvement, different deviations or deformities can develop. The most important malpositions are pes valgoplanus, pes cavus, heelfoot (pseudocavus), hallux flexus resp. rigidus, hallux valgus, forefoot adduction and claw or hammer toes. Combinations of several deviations occur frequently. Foot involvement influences the gait pattern. Usually the heel strike phase is shortened. The loading and push-off phases are disturbed according to the pattern of joint involvement and the resulting malpositions. A muscular imbalance develops which is mainly characterized by a hypertense tibialis anterior muscle and atrophy of the triceps sursae. Successful treatment requires adequate drug therapy as well as functionally oriented individual physiotherapy supported by foot adapted insoles and partial relief from weight-bearing.

Subtypes of HLA-DRB1*03, *08, *11, *12, *13 and *14 in early onset pauciarticular juvenile chronic arthritis (EOPA) with and without iridocyclitis.

A set of 200 patients with early onset pauciarticular juvenile chronic arthritis (EOPA-JCA) from Munich (165) and Prague (35) was investigated for the subtypes of HLA-DRB1*03, *08, *11, *12, *13 and *14. In addition, the relationship of DRB1, DQA1, DQB1 and DPB1 alleles with iridocyclitis in patients with EOPA-JCA was investigated. Subtyping for DRB1*03 was not informative, as all DR3 positive patients and all except one of the controls possessed DRB1*0301. Thus, the role of DRB1*0302 could not be assessed. The subtypes for DRB1*12, *13, and *14 did not reveal any statistically significant difference between patients and controls. In contrast, the subtype DRB1*1104 was the one most strongly associated with EOPA-JCA (chi 2 31.2, p value < 10(-6)). It appears that the subtype DRB1*1103 may also be associated with EOPA-JCA. The association of EOPA-JCA with DR8 is almost exclusively due to the subtype *0801. For the other alleles *0802, *0803, and *0804 there is no evidence for or against involvement in JCA. The analysis of iridocyclitis in EOPA-JCA revealed that DRB1*1104 is not more frequent in patients with eye disease than in patients without eye disease. The presence of DRB1*01 appears to convey some protective effect against the occurrence of iridiocylitis in EOPA-JCA, as had been previously observed by Melin-Aldana et al.

Five year follow-up of a prospective cohort of juvenile chronic arthritis with recent onset.

One hundred and fifty children with unsuspected juvenile chronic arthritis (JCA) and a disease duration of 3-6 months entered a prospective study. Diagnosis of JCA could be verified in 107 patients according to the WHO-EULAR criteria. After 5.0 +/- 0.9 years 66 of the 107 patients showed no disease activity, 24 of them for more than 2 years, 23 for less than 2 years without any drug therapy. Nineteen patients were still on NSAIDs and/or long acting drugs, 14 patients with unfavourable morphologic outcome (greater than stage II) and 17 patients with severe functional impairment (greater than or equal to stage III) all belonged to the 41 children with still active disease after 5 years follow-up. The disease course was polyarticular in 10 of the 14 patients with severe radiologic changes and in 14 of the 17 with unfavourable functional results. The wrist joint proved especially vulnerable since 46% of the severe radiologic changes concerned this joint. All 4 children with positive rheumatoid factor followed a polyarticular course with severe radiologic changes (stage greater than II), 3 of them together with unfavourable functional outcome. Risk factors for morphologically and functionally unfavourable course are therefore seen in a still active disease after 5 years, a polyarticular joint involvement and a positive rheumatoid factor. Extra-articular complications concerned chronic iridocyclitis in 7 patients, acute iridocyclitis in 2, amyloidosis in 1 and growth retardation in 2 children. -The prospective study is to be continued.

The effect of methotrexate and azathioprine on the serum levels of IgA-alpha 1-antitrypsin complex in juvenile chronic arthritis.

In the present study we investigated the influence of methotrexate (MTX) and azathioprine (AZA) on the serum levels of the IgA-alpha 1-antitrypsin (IgA-AT) complex in patients with the systemic form of juvenile chronic arthritis (JCA). Fifty-six JCA patients (22 treated with MTX, 18 treated with AZA, and 16 not treated with any immunosuppressive agent) were enrolled in the study. MTX dosage ranged from 0.3 to 0.5 mg/kg-1 week-1, while AZA was given daily at an average dose of 1 mg/kg. MTX was given for 13 months (SD = 7 months) whereas AZA for 11 months (SD = 6 months). The average value of the complex was higher in JCA patients than in both control groups (0.74 +/- 0.73 U vs 0.37 +/- 0.13 U (control children), P < 0.001 and vs 0.23 +/- 0.12 U (control adults), P < 0.001). Values exceeding the normal range were found in twenty-two JCA patients (39.4%). Serum IgA-AT level was lowest in the MTX group compared to AZA and non-treated patients (0.56 +/- 0.24 U, 0.76 = 0.43 U, 0.95 +/- 0.52 U, respectively, P < 0.05). IgA values exceeding normal levels for age were found in 14% of the patients. A correlation between the levels of the IgA-AT complex and C-reactive protein (r = 0.43, P < 0.01), alpha 1-acid-glycoprotein (r = 0.45, P < 0.01), alpha 1-antichymotrypsin (r = 0.52, P < 0.01), alpha 1-antitrypsin (r = 0.40, P < 0.01) and IgA (r = 0.56, P < 0.01) was established.

[Vasculitis in childhood]. / Die Vaskulitis im Kindesalter.

1. Vasculitis syndromes in children present with special features. The hypersensitivity vasculitides predominate with Henoch-Schoenlein purpura as a typical representative. Within the polyarteritis-nodosa-group we can distinguish an infantile form with involvement of coronary vessels. This disease resembles Kawasaki's syndrome. 2. The different vasculitis syndromes show a great variety in their clinical presentation; overlapping syndromes are possible. Diagnosis, however, is mostly based on clinical features, supported by laboratory data. In doubtful cases histologic and immunohistologic findings can prove helpful. Their diagnostic value should only be interpreted together with the clinical picture. Since specific findings are often missing we have to exclude all similar diseases. Especially systemic juvenile chronic arthritis, connective tissue diseases, several infections and sometimes malignancies have to be considered. 3. For the future we expect further differentiation and identification of new disease entities, thus hoping for a better classification.

[The treatment organization of rheumatic children and adolescents in West Germany]. / Zur Versorgungsstruktur rheumakranker Kinder und Jugendlicher in Westdeutschland.

Pediatric rheumatology represents a specialized subject which overlaps with important fields of pediatrics, as well as with adult rheumatology. As a speciality it includes age-specific rheumatologic diseases, an age-dependent differential diagnosis, special growth disturbances and joint deformities that are also influenced by age, and a subgroup of juvenile chronic arthritis. Socio-medical problems arise from a child's impaired physical and psychosocial development and their impact on education, the individual's choice of career, and effects on the patient's family. For pediatricians who are trained in this field and who treat only or predominantly children with rheumatic diseases the subspeciality of pediatric rheumatology should be introduced. In the future, precise figures on incidence and prevalence of juvenile rheumatic diseases in Germany must be obtained. Therapy of children with chronic arthritis affords improvement and further development by comprehensive training and further education of physicians and physiotherapists. Thus, it is important to take advantage of possibilities of inpatient and outpatient care, as well as the co-ordination of existing institutions. Arthralgias and acute rheumatic disorders in children present in a relatively high frequency. Chronic arthritis, however, is rare and treatment requires a supra-regional center for pediatric rheumatology. Quality of therapy for children with chronic rheumatic diseases must be considered prior to a locally oriented care. More intensive research is needed, with more clinical studies and basic research. More effort must be made to integrate analyse of musculoskeletal function and the importance of joint-deformity development into the research program. Further cooperation between pediatric rheumatology centers and universities would offer significant advantages in the future.

[Long-term artificial respiration in the treatment of neonatal tetanus (author's transl)]. / Zur Langzeitbeatmung des Neugeborenentetanus

A case of severe neonatal tetanus is reported which developed seven days after birth. The child was transferred to the intensive care unit where she was artificially ventilated for 25 days via a naso-tracheal catheter. The temperature and humidity of the inspired air were carefully controlled. Muscle relaxants and sedatives were given at 2-4 hours' interval.

[General and local growth disorders in chronic arthritis in childhood]. / Allgemeine und lokale Wachstumsstörungen bei chronischer Arthritis im Kindesalter.

In juvenile chronic arthritis both general and localized growth disorders are found. The general growth rate is especially impaired in the severe forms of the disease. In addition, delayed puberty with retarded pubertal growth spurt can temporarily result in growth retardation. Long term treatment with high dosage corticosteroids may intensify the growth failure, leading to severe stunting. Local growth disturbances are caused primarily in the area of the affected joints and secondarily as a result of functional disorders. The individual joints react in a specific, age-dependent manner. Growth acceleration and retardation, as well as various deformities of the bone structures, can be observed. Hands, knees and feet present typical examples of different growth disorders. In the toddler the inflammatory growth stimulus predominates first. This leads to accelerated ossification of the wrist and ankle as well as growth increase in knees, fingers and toes. In the further course and in the older child, shortening and growth reduction predominate. Here the premature fusion of the bones observed for example in fingers and toes, but also in the area of the distal part of the ulna, plays an important role. Arthritis can lead to deformities in all the joints. These deformities are more severe in children with early onset of the disease. Secondary growth disorders are caused by minor use of the joints. When wrists or elbows are involved, the entire hand may remain smaller. In the feet the growth impairment is often even more prominent, due to arthritis of the hips, knees or ankles. Both the general and the local growth disorders can be compensated to a large extent if treatment is begun at an early stage and the disease can be brought to remission. It is of great importance to preserve mobility of the joints in view of the interaction between function and growth.

[Psoriatic arthritis in childhood. A comparison with subgroups of chronic juvenile arthritis]. / Die Psoriasisarthritis im Kindesalter. Ein Vergleich mit den Subgruppen der juvenilen chronischen Arthritis.

We report on 48 children, 27 boys and 21 girls, with juvenile psoriatic arthritis. Onset during childhood differs in many ways from adult psoriatic arthritis. However, we detected a striking similarity to the subgroups of juvenile chronic arthritis in our patients. Pauciarticular onset was most prominent. Eight children presented with an early onset pauciarthritis, 33 patients showed a pauciarthritis type II with onset during school age; eight of them developed spondylarthritis with sacroiliitis. A seronegative polyarthritis was seen in six children. One girl suffered from seropositive disease. The diagnosis of psoriatic arthritis in childhood is often delayed since arthritis precedes psoriasis in many patients. In the absence of skin lesions the typical nail changes and a family history of psoriasis could suggest the diagnosis, especially in patients with an asymmetric arthritis and dactylitis.

[Course and prognosis of systemic juvenile chronic arthritis--retrospective study of 187 patients]. / Verlauf und Prognose der systemischen juvenilen chronischen Arthritis-- Retrospektive Studie an 187 Patienten.

The course of disease in 187 patients with systemic juvenile chronic arthritis was documented in a retrospective study 2-20 years after onset. Despite differences in joint involvement in the first 6 months of the disease, most of the patients subsequently developed a polyarthritis leading to severely impaired function in approximately 50% of them. Advanced degenerative changes identified by roentgenography were found in particular in the wrist and hip joints. There was an overall regression in the frequency of the extra-articular symptoms and the humoral pathologic activity. Fifteen years after the onset of disease only 30% of the patients still had systemic signs, and humoral activity was found in less than 50%. The mortality rate of 14% was primarily due to infections and kidney failure in amyloidosis. The course varies considerably from child to child. It has not so far been possible to differentiate prognostic factors for different subgroups.

Methotrexate therapy in juvenile rheumatoid arthritis: a retrospective study.

Nineteen selected patients with severe, mostly systemic onset, juvenile rheumatoid arthritis were treated with methotrexate (MTX) for an average of 10.5 months. Twelve patients showed statistically significant improvement, as measured by the number of affected, swollen, tender, and functionally impaired joints, and by decreases in erythrocyte sedimentation rate and C-reactive protein and an increase in hemoglobin level. Systemic manifestations improved in 6 of 8 patients. In 10 children receiving corticosteroids, the dosage was reduced. Seven patients did not respond to MTX therapy. Six of them showed an unchanged disease course, and 1 had a relapse after 4 months of MTX treatments. Probable side effects included gastrointestinal symptoms, elevated liver enzymes, and herpes zoster infection. MTX treatment should be considered for children with life-threatening or severe disabling arthritis that is unresponsive to other therapy.